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Biomedicines 2015, 3(2), 182-200; doi:10.3390/biomedicines3020182

Regulation of DNA Damage Response by Estrogen Receptor β-Mediated Inhibition of Breast Cancer Associated Gene 2

1
Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
2
Department of Radiation Oncology, Center for Radiological Research, Columbia University Medical Center, New York, NY 10032, USA
3
Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA
4
Department of Ophthalmology, Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Kenneth Cornetta
Received: 20 January 2015 / Revised: 26 March 2015 / Accepted: 13 April 2015 / Published: 21 April 2015
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Abstract

Accumulating evidence suggests that ubiquitin E3 ligases are involved in cancer development as their mutations correlate with genomic instability and genetic susceptibility to cancer. Despite significant findings of cancer-driving mutations in the BRCA1 gene, estrogen receptor (ER)-positive breast cancers progress upon treatment with DNA damaging-cytotoxic therapies. In order to understand the underlying mechanism by which ER-positive breast cancer cells develop resistance to DNA damaging agents, we employed an estrogen receptor agonist, Erb-041, to increase the activity of ERβ and negatively regulate the expression and function of the estrogen receptor α (ERα) in MCF-7 breast cancer cells. Upon Erb-041-mediated ERα down-regulation, the transcription of an ERα downstream effector, BCA2 (Breast Cancer Associated gene 2), correspondingly decreased. The ubiquitination of chromatin-bound BCA2 was induced by ultraviolet C (UVC) irradiation but suppressed by Erb-041 pretreatment, resulting in a blunted DNA damage response. Upon BCA2 silencing, DNA double-stranded breaks increased with Rad51 up-regulation and ataxia telangiectasia mutated (ATM) activation. Mechanistically, UV-induced BCA2 ubiquitination and chromatin binding were found to promote DNA damage response and repair via the interaction of BCA2 with ATM, γH2AX and Rad51. Taken together, this study suggests that Erb-041 potentiates BCA2 dissociation from chromatin and co-localization with Rad51, resulting in inhibition of homologous recombination repair. View Full-Text
Keywords: BCA2; DNA damage response; Erb-041; Rad51; UVC BCA2; DNA damage response; Erb-041; Rad51; UVC
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lee, Y.-H.; Sun, Y.; Gerweck, L.E.; Glickman, R.D. Regulation of DNA Damage Response by Estrogen Receptor β-Mediated Inhibition of Breast Cancer Associated Gene 2. Biomedicines 2015, 3, 182-200.

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